Multifunctional low-density lipoprotein nanoplatforms

多功能低密度脂蛋白纳米平台

• 批准号: 7245112
• 负责人: GANG ZHENG
• 金额: $ 15万
• 依托单位: UNIVERSITY HEALTH NETWORK
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-12 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7245112
• 关键词: Affinity; Anatomy; Applications Grants; Binding; Biocompatible; Blood Circulation; Cancer Detection; Cells; Cholesterol; Detection; Fluorescent Probes; Folic Acid; Gadolinium DTPA; Gadopentetate Dimeglumine; Goals; Label; Lipids; Lipoproteins; Low Density Lipoprotein Receptor; Low-Density Lipoproteins; Magnetic Resonance Imaging; Malignant Neoplasms; Modification; Nanostructures; Pathway interactions; Phase; Phospholipids; Photochemotherapy; Resolution; Reticuloendothelial System; Signal Transduction; Solutions; Specificity; Surface; Testing; Toxic effect; apolipoprotein B-100; base; biomaterial compatibility; cancer cell; concept; design; folate-binding protein; imaging probe; immunogenic; monolayer; nanodevice; novel; particle; prototype; receptor binding; scavenger receptor; tumor

DESCRIPTION (provided by applicant): Lipoproteins are naturally-existing nanostructures (8 - 1000 nm) responsible for the transport of cholesterol and other lipids in the blood circulation. Being endogenous carriers, lipoproteins are not immunogenic and escape recognition by the reticuloendothelial system. This project will initiate a broad exploration of lipoprotein particles as diverse and biocompatible nanoplatforms, focusing on low-density lipoprotein (LDL) (22nm) as a prototype. In our multifunctional LDL-based nanoplatform (LBNP) design, the diverse targeting is achieved by conjugating certain tumor-homing molecules to the receptor-binding Lys residues exposed on the apoB-100 surface of LDL. This turns off the LDL receptor (LDLR) binding and redirects the resulting LBNP to cancer cells or tumor vasculature via other cancer signatures. The LBNP multifunctionality is achieved by incorporating near-infrared fluorescent (NIRF)/photodynamic therapy (PDT) agents and magnetic resonance imaging (MRI) probes, respectively, into the LBNP lipid core and on its phospholipids monolayer. Thus, accumulation of the MRI/NIRF probes in target cells provides a facile mechanism for amplification of the MRI/NIRF detectable signal and affords opportunities to combine the strength of both MRI (high resolution/anatomic) and NIRF (high sensitivity), whereas the selective delivery of PDT agents to tumors via these pathways also provides a facile transition between cancer detection and treatment. During the R21 phase of the grant proposal (year 01), proof-of-feasibility of the LBNP concept will be provided by conjugating folic acid to LDL to achieve high affinity toward the folate receptor. In the R33 phase (year 02 to 04), the goal is to demonstrate the binding specificity of LBNP to folate receptors and to bring new functions to the LBNP particles thereby generating two novel folate receptor-targeted nanodevices: NIR dyereconstituted LBNP for NIRF/PDT and Gd-DTPA labeled LBNP for MRI. The key questions that will be tested are: 1) Will the stability of LDL particles be compromised by the proposed LDL modifications? 2) Can folic acid-conjugated LBNP bind to folate receptor specifically without binding to LDLR and/or LDL-scavenger receptor? 3) Can folate receptor binding affinity of LBNP be maximized using the multivalency effect? 4) Can the LBNP payload be high enough to exceed the intracellular MRI detection limit? This approach is expected to generate non-immunogenic multifunctional lipoprotein nanoplatforms, thus providing a solution to common problems associated with most synthetic nanodevices, namely biocompatibility and toxicity issues.

描述（由申请人提供）： 脂蛋白是天然存在的纳米结构（8 - 1000 nm），负责在血液循环中运输胆固醇和其他脂质。作为内源性载体，脂蛋白不具有免疫原性并且逃避网状内皮系统的识别。该项目将启动对脂蛋白颗粒作为多样化和生物相容性纳米平台的广泛探索，重点关注低密度脂蛋白（LDL）（22nm）作为原型。在我们基于 LDL 的多功能纳米平台 (LBNP) 设计中，通过将某些肿瘤归巢分子与 LDL apoB-100 表面暴露的受体结合赖氨酸残基缀合来实现多样化靶向。这会关闭 LDL 受体 (LDLR) 结合，并通过其他癌症特征将产生的 LBNP 重定向至癌细胞或肿瘤脉管系统。 LBNP 的多功能性是通过将近红外荧光 (NIRF)/光动力治疗 (PDT) 试剂和磁共振成像 (MRI) 探针分别结合到 LBNP 脂质核心及其磷脂单层上来实现的。因此，MRI/NIRF探针在靶细胞中的积累提供了一种放大MRI/NIRF可检测信号的简便机制，并提供了结合MRI（高分辨率/解剖）和NIRF（高灵敏度）强度的机会，而通过这些途径将PDT药物选择性递送至肿瘤也提供了癌症检测和治疗之间的简便过渡。在拨款提案的 R21 阶段（第 01 年），将通过将叶酸与 LDL 结合以实现对叶酸受体的高亲和力来提供 LBNP 概念的可行性证明。 R33阶段（02年至04年）的目标是证明LBNP与叶酸受体的结合特异性，并为LBNP颗粒带来新功能，从而产生两种新型叶酸受体靶向纳米器件：用于NIRF/PDT的NIR染料重组LBNP和用于MRI的Gd-DTPA标记的LBNP。将测试的关键问题是：1）所提出的 LDL 修饰是否会损害 LDL 颗粒的稳定性？ 2) 叶酸结合的 LBNP 能否特异性结合叶酸受体而不结合 LDLR 和/或 LDL 清除剂受体？ 3) 能否利用多价效应最大化 LBNP 的叶酸受体结合亲和力？ 4) LBNP 有效负载是否足够高以超过细胞内 MRI 检测极限？这种方法有望产生非免疫原性多功能脂蛋白纳米平台，从而为与大多数合成纳米器件相关的常见问题（即生物相容性和毒性问题）提供解决方案。